[ CAS No. 452-78-8 ] {[proInfo.proName]}

Name: 452-78-8|3-Fluoro-4-methylphenol|97%
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Quality Control of [ 452-78-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 452-78-8 ]

Product Details of [ 452-78-8 ]

CAS No. :	452-78-8	MDL No. :	MFCD00143164
Formula :	C₇H₇FO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GJOOCAXPERKNMN-UHFFFAOYSA-N
M.W :	126.13	Pubchem ID :	2774613
Synonyms :

Calculated chemistry of [ 452-78-8 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.39
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.59
Log Po/w (XLOGP3) :	2.03
Log Po/w (WLOGP) :	2.26
Log Po/w (MLOGP) :	2.24
Log Po/w (SILICOS-IT) :	2.25
Consensus Log Po/w :	2.07

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.39
Solubility :	0.509 mg/ml ; 0.00403 mol/l
Class :	Soluble
Log S (Ali) :	-2.08
Solubility :	1.04 mg/ml ; 0.00827 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.45
Solubility :	0.451 mg/ml ; 0.00357 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 452-78-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P273-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H319-H412	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 452-78-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 452-78-8 ]
Downstream synthetic route of [ 452-78-8 ]

[ 452-78-8 ] Synthesis Path-Upstream 1~8

1
[ 452-77-7 ]
[ 452-78-8 ]

Yield	Reaction Conditions	Operation in experiment
44.8%	at 0 - 80℃; for 6 h;	Preparation of 3-fluoro-4-methylphenol: 3-Fluoro-4-methylaniline (5g, 39.95 lmmol) was dissolved in 10percent sulfuric acid aqueous solution (100ml). Thereafter, the temperature was lowered to O°C. thereto sodium nitrate (5.5g, 79.902mmol) was added, and the reaction mixture was stirred at same temperature for 30 minutes. Then the reaction mixture was stirred at 50⁰C for 30 minutes, and the last time, stirred at 8O°C for 5 hours. Ice water was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate = 8:1) to give 2.26g (yield: 44.8percent, colorless oil) of the target compound.¹H NMR(400MHz, CDCl₃): 6.98(t, J=8.6Hz, IH), 6.52(m, 2H), 5.82(br, IH),2.12(s, 3H).

Reference： [1] Patent: WO2007/8037, 2007, A1, . Location in patent: Page/Page column 34-35
[2] Journal of the Chemical Society, 1949, p. Spl. 113
[3] Journal of the American Chemical Society, 1950, vol. 72, p. 1806

2
[ 405-06-1 ]
[ 331746-01-1 ]
[ 452-78-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With boron tribromide In dichloromethane	To a -70° C. solution of 3-fluoro-4-methyl anisole (1.62 g; 11.6 mmol) in CH₂Cl₂ (10 mL) was added dropwise BBr₃ (10 mL; 12 mmol). The reaction mixture was stirred at -70° C. for 10 min, then allowed to warm to 0° C. and stirred at 0° C. for 2 h. The reaction was allowed to warm to RT and concentrated in vacuo and the residue was partitioned between H₂O and EtOAc. The organic phase was washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo to give 3-fluoro-4-methyl phenol (1.1 g; 75percent) as an oil.

Reference： [1] Patent: US6414002, 2002, B1,

3
[ 1427-07-2 ]
[ 452-78-8 ]

Reference： [1] Journal of the American Chemical Society, 1950, vol. 72, p. 1806
[2] Journal of the Chemical Society, 1949, p. Spl. 113

4
[ 452-78-8 ]
[ 74-88-4 ]
[ 405-06-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h; Inert atmosphere	To a solution of 1.00 g (7.93 mmol) of 3-fluoro-4-methylphenol in 20 ml of dehydrated DMF, 3.30 g (23.9 mmol) of potassium carbonate and 0.750 ml (12.0 mmol) of methyl iodide were added at room temperature in an argon atmosphere and reacted at room temperature for 16 hours with stirring. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate=100:0→80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 725 mg of the title compound (yield: 65percent) as a colorless oil. Mass spectrum (CI, m/z): 141 [M+1]⁺. ¹H-NMR spectrum (400 MHz, CDCl₃) δ: 7.10-7.01 (m, 1H), 6.62-6.55 (m, 2H), 3.77 (s, 3H), 2.21-2.18 (m, 3H).

Reference： [1] Patent: US2018/186818, 2018, A1, . Location in patent: Paragraph 1130; 1131; 1132; 1133; 1134

5
[ 452-78-8 ]
[ 77-78-1 ]
[ 405-06-1 ]

Reference： [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 42, p. 9943 - 9947

6
[ 452-78-8 ]
[ 405-06-1 ]

Reference： [1] Journal of the American Chemical Society, 1950, vol. 72, p. 1806

7
[ 452-78-8 ]
[ 394-42-3 ]

Reference： [1] Journal of the American Chemical Society, 1950, vol. 72, p. 1806

8
[ 452-78-8 ]
[ 314298-13-0 ]

Reference： [1] Patent: US2017/112833, 2017, A1,

[ 452-78-8 ] Synthesis Path-Downstream 1~79

1
[ 452-78-8 ]
[ 405-06-1 ]

Reference： [1]Journal of the American Chemical Society,1950,vol. 72,p. 1806

2
[ 452-77-7 ]
[ 452-78-8 ]

Yield	Reaction Conditions	Operation in experiment
44.8%	With sodium nitrate; sulfuric acid; water; at 0 - 80℃; for 6h;	Preparation of 3-fluoro-4-methylphenol: 3-Fluoro-4-methylaniline (5g, 39.95 lmmol) was dissolved in 10% sulfuric acid aqueous solution (100ml). Thereafter, the temperature was lowered to OC. thereto sodium nitrate (5.5g, 79.902mmol) was added, and the reaction mixture was stirred at same temperature for 30 minutes. Then the reaction mixture was stirred at 500C for 30 minutes, and the last time, stirred at 8OC for 5 hours. Ice water was added to quench the reaction, and aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate = 8:1) to give 2.26g (yield: 44.8%, colorless oil) of the target compound.1H NMR(400MHz, CDCl3): 6.98(t, J=8.6Hz, IH), 6.52(m, 2H), 5.82(br, IH),2.12(s, 3H).

Reference： [1]Patent: WO2007/8037,2007,A1 .Location in patent: Page/Page column 34-35
[2]Journal of the Chemical Society,1949,p. Spl. 113
[3]Journal of the American Chemical Society,1950,vol. 72,p. 1806

3
[ 452-78-8 ]
[ 83341-28-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With nitric acid; In dichloromethane; water; at 20℃; for 0.5h;	70% Nitric acid (0.759 ml_, 8.42 mmol) was added dropwise to a solution of 3-fluoro-4- methylphenol (966 mg, 7.66 mmol) in dichloromethane (25 mL) at rt. The reaction was stirred for 30 min before being washed with water. The aqueous layer was extracted with dichloromethane (1x) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow/orange solid. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia /9.5% methanol /90% dichloromethane) to give 5-fluoro-4-methyl-2-nitrophenol (D21 , 873 mg, 67 % yield) as a yellow solid.1H NMR delta (CDCI3, 400 MHz) 2.60 (3 H, s), 6.80 (1 H, d, J 10), 7.99 (1 H, dd, J 10 and 0.8).
66%	With nitric acid; In dichloromethane; at 20℃; for 1h;	(0662) 3-Fluoro-4-methylphenol (5.0 g, 39.7 mmol) was dissolved in dichloromethane (100 mL), and nitric acid (70%, 5 mL) was added to the system. The reaction was carried out at room temperature for 1 h. After the reaction, the mixture was washed with water (50 mL×2). The organic phase was dried with anhydrous sodium sulfate, filtrated, and concentrated to get the title compound (4.48 g, yield: 66%).
57%	With tetrabutylammomium bromide; nitric acid; In water; 1,2-dichloro-ethane; at 20℃; for 4h;	<strong>[452-78-8]3-fluoro-4-methylphenol</strong> (3.66 g, 29.0 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. HNO3 70% (3.7 mL, 58 mmol) was diluted with H2O (33 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture, which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) delta ppm 11.10 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 6.85 (d, J=11.0 Hz, 1H), 2.13 (s, 3H).

57%	With tetrabutylammomium bromide; nitric acid; In 1,1-dichloroethane; water; at 20℃; for 4h;	Intermediate B110: 5-methyl-4-[4-(1-methylethyl)-1-piperazinyl]-2- (methyloxy)aniline; Step A/Intermediate B1 11 : 5-fluoro-4-methyl-2-nitrophenol<strong>[452-78-8]3-fluoro-4-methylphenol</strong> (3.66 g, 29.0 mmol) was dissolved in dichloroethane (32 ml.) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. Nitric acid 70% (3.7 ml_, 58 mmol) was diluted with water (33 ml.) to make a 7% nitric acid solution. This solution was added to the reaction mixture which was then stirred at room temperature for 4h at which time the reaction was judged complete by TLC. The reaction was poured into water and extracted with dichloromethane (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica gel and purified by chromatography on SiO2 to give 5-fluoro-4-methyl-2-nitrophenol as a yellow solid (2.83 g, 57%). 1 H NMR (400 MHz, DMSOd6) delta ppm 11.10 (s, 1 H), 7.89 (d, J=8.1 Hz, 1 H), 6.85 (d, J=11.0 Hz, 1 H), 2.13 (s, 3 H).
57%	With nitric acid;tetrabutylammomium bromide; In water; 1,2-dichloro-ethane; at 20℃; for 4h;Inert atmosphere;	3-Fluoro-4-methylphenol (3 66 g, 29 0 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0 935 g, 2 90 mmol) was added HNO3 70% (3 7 mL,10 58 mmol) was diluted with H2O (33 mL) to make a 7% HNO3 solution This solution was added to the reaction mixture, which was then stirred at rt for 4h at which time the reaction was judged complete by TLC The reaction was poured into H2O and extracted with DCM (3x) The combined organic layers were dried over MgSO4 , filtered and concentrated in vacuo The resulting residue was adsorbed onto silica15 gel and flash chromatographed to give the title compound of step B (2 83 g, 57%) 1H-NMR (400 MHz, DMSO-Cf6) delta ppm 11 10 (s, 1 H), 7 89 (d, J = 8 1 Hz, 1 H), 6 85 (d, J = 11 O Hz, 1 H), and 2 13 (s, 3 H)

Reference： [1]Liebigs Annalen der Chemie,1982,p. 1423 - 1433
[2]Patent: WO2009/37294,2009,A1 .Location in patent: Page/Page column 74
[3]Patent: US2017/112833,2017,A1 .Location in patent: Paragraph 0661-0662
[4]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 122
[5]Patent: WO2009/20990,2009,A1 .Location in patent: Page/Page column 142
[6]Patent: WO2010/104899,2010,A1 .Location in patent: Page/Page column 108

Yield	Reaction Conditions	Operation in experiment
		A Grignard reagent prepared from 4-boromo-2-fluorotoluene (25 g, 130 mmol) and magnesium (3.5 g, 140 mmol) by a conventional method was added to a THF solution (200 ml) of trimethyl borate (30 ml, 260 mmol) at a room temperature. After further stirring a night at a room temperature, a 3M hydrochloric acid aqueous solution (100 ml) was added thereto at -20 C. or lower, and the solution was stirred at a room temperature for 2 hours. Brine (150 ml) was added to this reaction mixture, and the solution was extracted with ether (150 ml*2). The solution was dried on anhydrous magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure, followed by adding heptane (100 ml) to filter non-dissolved crystal off. A 31% hydrogen peroxide aqueous solution (31 ml) was added to a THF solution (300 ml) of the unrefined boric acid derivative (24 g, 160 mmol) obtained above at 0 C., and the solution was stirred a day at a room temperature. A 5% sodium thiosulfate aqueous solution (50 ml) was carefully added to this reaction mixture. 3N hydrochloric acid (100 ml) was further added to the reaction solution, and then the organic layer was separated. The aqueous layer was further extracted with toluene (200 ml), and the organic layers were put together and washed with water (200 ml), followed by drying on anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure, and the residue was refined by distillation under reduced pressure (60 C./4.0 mm Hg) to obtain 3-fluoro-4-methylphenol 10 g (60%).

5
[ 32315-10-9 ]
[ 452-78-8 ]
[ 331746-01-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With pyridine; In diethyl ether; dichloromethane; at 0 - 20℃; for 3.25h;Heating / reflux;	Synthesis of 3-fluoro-4-methylphenyl carbonochloridate (2) A 1 L 3-necked round bottom flask equipped with a mechanic stirrer was charged with <strong>[452-78-8]3-fluoro-4-methylphenol</strong> 1 (50 g, 446 mmol), triphosgene (43.67 g, 147 mmol) and CH2Cl2 (400 mL). Pyridine (35.2 g, 446 mmol) was added dropwise at 0 C. under N2 over a period of 30 minutes. The reaction mixture was allowed to warm to room temperature over 45 minutes, and then stirred at reflux for an additional 2 hours. The reaction was cooled to room temperature, and the solvents were removed in vacuo. Anhydrous Et2O (200 mL) was added to the residue, and the resulting slurry was filtered. The filtrate was concentrated in vacuo to afford crude 3-fluoro-4-methylphenyl chloroformate (83.5 g, 99% yield) as a thick oil, which was immediately used in the next step without further purification.

Reference： [1]Patent: US2008/9534,2008,A1 .Location in patent: Page/Page column 15

6
[ 452-78-8 ]
[ 83341-37-1 ]

Reference： [1]Liebigs Annalen der Chemie,1982,p. 1423 - 1433

7
[ 452-78-8 ]
[ 83341-49-5 ]

Reference： [1]Liebigs Annalen der Chemie,1982,p. 1423 - 1433

8
[ 452-78-8 ]
Naphthalene-1,4-dicarboxylic acid bis-[(4-fluoro-2-hydroxy-5-methyl-phenyl)-amide] [ No CAS ]

Reference： [1]Liebigs Annalen der Chemie,1982,p. 1423 - 1433

9
[ 452-78-8 ]
[ 394-42-3 ]

Reference： [1]Journal of the American Chemical Society,1950,vol. 72,p. 1806

10
[ 1427-07-2 ]
[ 452-78-8 ]

Reference： [1]Journal of the American Chemical Society,1950,vol. 72,p. 1806
[2]Journal of the Chemical Society,1949,p. Spl. 113

11
[ 405-06-1 ]
[ 331746-01-1 ]
[ 452-78-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With boron tribromide; In dichloromethane;	To a -70 C. solution of 3-fluoro-4-methyl anisole (1.62 g; 11.6 mmol) in CH2Cl2 (10 mL) was added dropwise BBr3 (10 mL; 12 mmol). The reaction mixture was stirred at -70 C. for 10 min, then allowed to warm to 0 C. and stirred at 0 C. for 2 h. The reaction was allowed to warm to RT and concentrated in vacuo and the residue was partitioned between H2O and EtOAc. The organic phase was washed with H2O, dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methyl phenol (1.1 g; 75%) as an oil.

Reference： [1]Patent: US6414002,2002,B1

12
[ 452-78-8 ]
3-fluoro-4-methyl-1-(methoxymethoxy)-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		G 6 2-Fluoro-4-methoxymethoxy-toluene as an oil from <strong>[452-78-8]3-fluoro-4-methyl-phenol</strong> (H2). MS: 170 (M) IR: 2956, 1630, 1590, 1510, 1265, 1153, 1012, 850 Anal. calc. for C9 H11 O2 F (170.183): C 63.52, H 6.52; found: C 63.25, H 6.52.

Reference： [1]Patent: US5583222,1996,A

13
[ 50-00-0 ]
[ 452-78-8 ]
[ 920525-52-6 ]
[ 504414-06-6 ]

Yield	Reaction Conditions	Operation in experiment
11.5%; 48.0%		Step 2. Preparation of 4-fluoro-2-hydroxy-5-methyl-benzaldehyde and 2-fluoro-6-hydroxy-3-methyl-benzaldehyde: The compound (2.26g, 17.920mmol) prepared in the step 1, was dissolved in magnesium methoxide in methanol solution (14.2ml, 10.762mmol, 8% wt in MeOH). Thereafter the reaction mixture was distilled until the methanol was left over about half point, thereto the reaction mixture was added toluene, and distilled when the reaction temperature was reached 95C. p-Formaldehyde (1.66g, 155.18mmol) was slowly added for 1 hour, and then the reaction mixture was distilled for 1 hour, and cooled down room temperature. Then 10% sulfuric acid (20ml) was added, stirred at 350C for 2 hours. Ice water was added to quench the reaction and aqueous layer was extracted with toluene. Combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate = 13:1) to give 1.25g (yield: 48.0%, colorless oil) of compound A and 0.3g (yield: 11.5%, colorless oil) of compound B. 1H NMR(400MHz, CDCl3, compound A): delta 11.15(s, IH), 9.98(s, IH), 7.36(d, J=8.4Hz, IH), 6.63(d, J=10.8Hz, IH), 2.23(s, 3H). 1H NMR(400MHz, CDCl3, compound B): delta 11.28(s, IH), 10.26(s, IH), 7.32(m,IH), 6.67(d, J=8.4Hz, IH), 2.10(s, 3H).

Reference： [1]Patent: WO2007/8037,2007,A1 .Location in patent: Page/Page column 35

14
[ 934180-37-7 ]
[ 452-78-8 ]
C₂₀H₂₈FNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 12h;	Diethylazodicarboxylate (87 mg, 78 mul_, 0.497 mmol) was added dropwise to a solution of enalphafo-3-hydroxy-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid terf-butyl ester (100 mg, 0.414 mmol), triphenylphosphine (130 mg, 0.497 mmol) and <strong>[452-78-8]3-fluoro-4-methylphenol</strong> (63 mg, 0.497 mmol) in THF (4 ml_). The reaction mixture was stirred under a nitrogen atmosphere for 12 h at ambient temperature. Volatiles were removed under reduced pressure. The resultant oil was dissolved in dichloromethane (2 ml_), trifluoroacetic acid (1 ml.) added and the reaction mixture stirred at room temperature for 12 h. Volatiles were removed under reduced pressure, the crude product dissolved in methanol (4 mL) and the solution loaded onto a SCX cartridge (Phenomenex). The cartridge was eluted with methanol (20 mL) to remove triphenylphosphine oxide followed by elution with ammonia in methanol (2 M, 20 mL). Evaporation in vacuo afforded the crude product which was further purified by preparative reverse phase LCMS to afford exo-3-(3-fluoro-4- methylphenoxy)-9-azabicyclo[3.3.1]nonane trifluoroacetic acid salt (17 mg, 11 %). Data for exo-3-(3-fluoro-4-methylphenoxy)-9-azabicyclo[3.3.1]nonane trifluoroacetic acid salt: MS (ESI) m/z: 250 ([M+H] +).

Reference： [1]Patent: WO2007/39563,2007,A1 .Location in patent: Page/Page column 50

15
[ 299176-17-3 ]
[ 452-78-8 ]
[ 1072003-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;	General procedure: NaH (30.0mmol) was added to a solution of 1 (8.60g, 30.0mmol) and substituted phenol (30.0mmol) in DMF (150mL) at room temperature under N2, and the mixture was stirred at 80C for 10h. Water was added to the cooled mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain purified compound 9, or crude 9 was used directly for the next reaction without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5079 - 5098

16
[ 452-78-8 ]
[ 33742-70-0 ]
[ 1072004-53-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;	General procedure: NaH (12.0mmol) was added to a solution of 1 or 722 (1.88g, 10.0mmol) and substituted phenol (12.0mmol) in DMF (50mL) at room temperature under N2, and the mixture was stirred at 80C for 10h. Water was added to the cooled mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain purified compound 2, or crude 2 was used directly for the next reaction without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5099 - 5117

17
[ 934180-37-7 ]
[ 452-78-8 ]
[ 76-05-1 ]
exo-3-(3-fluoro-4-methylphenoxy)-9-azabicyclo[3.3.1]nonane trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		Diethylazodicarboxylate (87 mg, 78 muL, 0.497 mmol) was added dropwise to a solution of endo-3-hydroxy-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (100 mg, 0.414 mmol), triphenylphosphine (130 mg, 0.497 mmol) and <strong>[452-78-8]3-fluoro-4-methylphenol</strong> (63 mg, 0.497 mmol) in THF (4 mL). The reaction mixture was stirred under a nitrogen atmosphere for 12 h at ambient temperature. Volatiles were removed under reduced pressure. The resultant oil was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) added and the reaction mixture stirred at room temperature for 12 h. Volatiles were removed under reduced pressure, the crude product dissolved in methanol (4 mL) and the solution loaded onto a SCX cartridge (Phenomenex). The cartridge was eluted with methanol (20 mL) to remove triphenylphosphine oxide followed by elution with ammonia in methanol (2 M, 20 mL). Evaporation in vacuo afforded the crude product which was further purified by preparative reverse phase LCMS to afford exo-3-(3-fluoro-4-methylphenoxy)-9-azabicyclo[3.3.1]nonane trifluoroacetic acid salt (17 mg, 11%). Data for exo-3-(3-fluoro-4-methylphenoxy)-9-azabicyclo[3.3.1]nonane trifluoroacetic acid salt: MS (ESI) m/z: 250 ([M+H]+).

Reference： [1]Patent: US2007/112019,2007,A1 .Location in patent: Page/Page column 27/2

18
[ 452-78-8 ]
[ 1262046-34-3 ]